Epistatic and independent functions of Caspase-3 and Bcl-X L in developmental programmed cell death

• DOI: 10.1073/pnas.97.1.466
• Publication Date: 2002-07-26T14:38:21Z
• Authors: K. A. Roth; C.-Y. Kuan; T. F. Haydar; C. D'Sa-Eipper; K. S. Shindler; T. S. Zheng; K. Kuida; R. A. Flavell; P. Rakic
• Keywords: Mice, Knockout; Neurons; 0301 basic medicine; Genotype; Caspase 3; Histocytochemistry; Stem Cells; bcl-X Protein; Brain; Gene Expression Regulation, Developmental; Apoptosis; Nervous System; 3. Good health; Mice; 03 medical and health sciences; Phenotype; Proto-Oncogene Proteins c-bcl-2; Caspases; Mutation; In Situ Nick-End Labeling; Animals; Cells, Cultured

The number of neurons in the mammalian brain is determined by a balance between cell proliferation and programmed cell death. Recent studies indicated that Bcl-X L prevents, whereas Caspase-3 mediates, cell death in the developing nervous system, but whether Bcl-X L directly blocks the apoptotic function of Caspase-3 in vivo is not known. To examine this question, we generated bcl-x / caspase-3 double mutants and found that caspase-3 deficiency abrogated the increased apoptosis of postmitotic neurons but not the increased hematopoietic cell death and embryonic lethality caused by the bcl-x mutation. In contrast, caspase-3 , but not bcl-x , deficiency changed the normal incidence of neuronal progenitor cell apoptosis, consistent with the lack of expression of Bcl-X L in the proliferative population of the embryonic cortex. Thus, although Caspase-3 is epistatically downstream to Bcl-X L in postmitotic neurons, it independently regulates apoptosis of neuronal founder cells. Taken together, these results establish a role of programmed cell death in regulating the size of progenitor population in the central nervous system, a function that is distinct from the classic role of cell death in matching postmitotic neuronal population with postsynaptic targets.